PROJECT SUMMARY/ABSTRACT The primary goal of this proposal is to develop the principal investigator, Dr. Michael Thompson, into an independent physician scientist in the field of hepatology research. Michael has previously received PhD training in cellular and molecular pathology with a focus on liver disease. At the current time, he has completed clinical training in Pediatric Endocrinology and has designed a 5 year career development plan to provide additional training in bile acid metabolism and microbiome research. At the end of this career development award, he will become an independent investigator with his own lab program evaluating the developmental origins of liver disease. Dr. Nicholas Davidson, Chief of Gastroenterology at Washington University, will mentor the PI. Dr. Davidson is a well-known leader in intestinal and hepatic bile acid metabolism research and an experienced mentor. Dr. Phil Tarr, Chief of Pediatric Gastroenterology at Washington University, will serve as co-mentor for the PI. Dr. Tarr is a recognized leader in microbiome research which is a primary focus of this proposal. The PI will take advantage of the abundant basic science and clinical resources available at Washington University to develop his own clinically relevant basic research program. Obesity and its complications affect 78 million adults and 13 million children with an estimated economic impact of $2.0 trillion per year. Growing evidence supports that in utero and perinatal events drive risk for insulin resistance and obesity associated complications such as nonalcoholic fatty liver disease (NAFLD) in the offspring. Our preliminary findings indicate that alterations in bile acid homeostasis are associated with this increased risk. This proposal will focus on defining the mechanisms behind the observed alterations in bile acid homeostasis. I will utilize an established model of maternal high fat/high sugar diet exposure to test this hypothesis. In the first aim, I will evaluate cholesterol absorption, bile acid excretion, and bile acid metabolism/transport to define which are contributing to the increased bile acid pool size and composition. In the second aim, I will define whether vertical transmission of the microbiome occurs across generations and whether changes in the microbiome impact bile acid metabolism and metabolic liver disease in the offspring. In the third aim, I will evaluate the efficacy of targeting the bile acid pool size or pool composition as a preventative approach for metabolic liver disease offspring of obese dams. Specifically, I will treat offspring with a bile acid sequestrant (cholestyramine) or a hydrophilic bile acid (UDCA) prior to feeding a western diet, after which I will evaluate insulin resistance and steatosis. Identification of potentially pathogenic alterations in bile acid pool composition, metabolism, and/or transport will support further hypothesis driven research design to identify the mechanism of increased risk for disease progression. Once a mechanistic link is proven between altered bile acid metabolism in offspring and risk for NAFLD progression, this information will be used to design bile acid based preventative therapies to prevent disease progression in at risk patients.